Insulin binding to its receptor represents the earliest event in the initiation of insulin action in target tissues. Recent in vitro studies and studies with cell clones have shown that insulin receptor displays a tyrosine kinase activity that is enhanced upon insulin binding. This insulin-activated tyrosine kinase activity is correlated with the phosphorylation status of endogenous substrates, suggesting that this might be a mechanism whereby insulin transmits signals to target cells. A defect in the insulin receptor tyrosine kinase therefore might be associated with insulin resistance. Since insulin resistance may be a predictor of the development of type II diabetes, as suggested in studies in the Pima Indians, studies of the tyrosine kinase activity of the insulin receptor were undertaken in this population. Assays were set up to quantitatively measure insulin receptor concentration and tyrosine kinase activity in small pieces of skeletal muscle obtained by needle biopsy. Receptor concentration was estimated by 125I-insulin binding and Scatchard analysis. Tyrosine kinase activity was determined by phosphorylation of the synthetic peptide glutamine-tyrosine with 32P-labeled ATP. Muscle biopsies were done during a euglycemic, hyperinsulinemic clamp using two different insulin doses. The tyrosine kinase activity of the insulin receptor increased in vivo in a dose-dependent man and correlated with insulin sensitivity. Studies are currently ongoing to confirm the findings in a larger number of subjects.